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Angiogenesis for the Clinician

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Clinical and Basic Immunodermatology

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Abstract

Angiogenesis, the development of a microvasculature to a neoplastic, inflammatory, or infectious disease process, is a promising therapeutic target that has not been fully exploited. Virtually all processes of therapy impinge on cutaneous angiogenesis. A proper understanding of cutaneous pathophysiology, with respect to angiogenesis, will lead to a more effective use of current therapies for dermatologic diseases, as well as development of novel therapies. With this knowledge, the clinician can make educated guesses on the effect of therapy on a process. The primary disorders of the skin are infectious, inflammatory, and neoplastic. All of these categories are capable of inducing angiogenesis through a limited and overlapping subset of mechanisms, and these mechanisms can be understood by the practicing dermatologist. This chapter discusses the primary mediators of angiogenesis and examples of common skin disorders in which they occur. Antiangiogenic therapy is also discussed. Factors that directly impact endothelium are called direct angiogenesis stimulators or inhibitors, while factors that stimulate nonendothelial cells to make stimulators or inhibitors are called indirect angiogenesis stimulators and inhibitors.

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References

  1. Perry BN, Arbiser JL. The duality of angiogenesis: implications for therapy of human disease. J Invest Dermatol. 2006;126(10):2160–6.

    Article  CAS  PubMed  Google Scholar 

  2. Patterson BC, Sang QA. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9). J Biol Chem. 1997;272(46):28823–5.

    Article  CAS  PubMed  Google Scholar 

  3. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3(5):391–400.

    Article  CAS  PubMed  Google Scholar 

  4. Singh DV, Agarwal S, Singh P, Godbole MM, Misra K. Curcumin conjugates induce apoptosis via a mitochondrion dependent pathway in MCF-7 and MDA-MB-231 cell lines. Asian Pac J Cancer Prev. 2013;14(10):5797–804.

    Article  PubMed  Google Scholar 

  5. Hill-Kapturczak N, Thamilselvan V, Liu F, Nick HS, Agarwal A. Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells. Am J Physiol Renal Physiol. 2001;281(5):F851–9.

    Article  CAS  PubMed  Google Scholar 

  6. Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, Bornmann W, Sherman M, Kalman D. Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med. 2005;11(7):731–9.

    Article  CAS  PubMed  Google Scholar 

  7. Battle TE, Arbiser J, Frank DA. The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood. 2005;106(2):690–7.

    Article  CAS  PubMed  Google Scholar 

  8. Martin S, Lamb HK, Brady C, Lefkove B, Bonner MY, Thompson P, Lovat PE, Arbiser JL, Hawkins AR, Redfern CP. Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. Br J Cancer. 2013;109(2):433–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Agarwal R, Agarwal C, Ichikawa H, Singh RP, Aggarwal BB. Anticancer potential of silymarin: from bench to bed side. Anticancer Res. 2006;26(6B):4457–98.

    CAS  PubMed  Google Scholar 

  10. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91(9):4082–5.

    Google Scholar 

  11. Luo J, Gagne JJ, Landon J, Avorn J, Kesselheim AS. Comparative effectiveness and safety of thalidomide and lenalidomide in patients with multiple myeloma in the United States of America: a population-based cohort study. Eur J Cancer. 2016;70:22–33.

    Article  PubMed  Google Scholar 

  12. Perry BN, Govindarajan B, Bhandarkar SS, Knaus UG, Valo M, Sturk C, Carrillo CO, Sohn A, Cerimele F, Dumont D, Losken A, Williams J, Brown LF, Tan X, Ioffe E, Yancopoulos GD, et al. Pharmacologic blockade of angiopoietin-2 is efficacious against model hemangiomas in mice. J Invest Dermatol. 2006;126(10):2316–22.

    Article  CAS  PubMed  Google Scholar 

  13. Arbiser JL, Bips M, Seidler A, Bonner MY, Kovach C. Combination therapy of imiquimod and gentian violet for cutaneous melanoma metastases. J Am Acad Dermatol. 2012;67(2):e81–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stoff B, MacKelfresh J, Fried L, Cohen C, Arbiser JL. A nonsteroidal alternative to impetiginized eczema in the emergency room. J Am Acad Dermatol. 2010;63(3):537–9.

    Article  PubMed  Google Scholar 

  15. Arbiser JL, Kau T, Konar M, Narra K, Ramchandran R, Summers SA, Vlahos CJ, Ye K, Perry BN, Matter W, Fischl A, Cook J, Silver PA, Bain J, Cohen P, Whitmire D, et al. Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis. Blood. 2007;109(2):560–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Karlsson I, Zhou X, Thomas R, Smith AT, Bonner MY, Bakshi P, Banga AK, Bowen JP, Qabaja G, Ford SL, Ballard MD, Petersen KS, Li X, Chen G, Ogretmen B, Zhang J, et al. Solenopsin A and analogs exhibit ceramide-like biological activity. Vasc Cell. 2015;7:5.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Park J, Kaufmann GF, Bowen JP, Arbiser JL, Janda KD. Solenopsin A, a venom alkaloid from the fire ant Solenopsis invicta, inhibits quorum-sensing signaling in Pseudomonas aeruginosa. J Infect Dis. 2008;198(8):1198–201.

    Article  CAS  PubMed  Google Scholar 

  18. Dumont FJ, Su Q. Mechanism of action of the immunosuppressant rapamycin. Life Sci. 1996;58(5):373–95.

    Article  CAS  PubMed  Google Scholar 

  19. Govindarajan B, Willoughby L, Band H, Curatolo AS, Veledar E, Chen S, Bonner MY, Abel MG, Moses MA, Arbiser JL. Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia. Vasc Cell. 2012;4(1):11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation. 2004;77(5):760–2.

    Google Scholar 

  21. Mahnke A, Meier RJ, Schatz V, Hofmann J, Castiglione K, Schleicher U, Wolfbeis OS, Bogdan C, Jantsch J. Hypoxia in Leishmania major skin lesions impairs the NO-dependent leishmanicidal activity of macrophages. J Invest Dermatol. 2014;134(9):2339–46.

    Article  CAS  PubMed  Google Scholar 

  22. Arbiser JL, Byers HR, Cohen C, Arbeit J. Altered basic fibroblast growth factor expression in common epidermal neoplasms: examination with in situ hybridization and immunohistochemistry. J Am Acad Dermatol. 2000;42(6):973–7.

    Article  CAS  PubMed  Google Scholar 

  23. Leaute-Labreze C, de la Dumas RE, Hubiche T, Boralevi F, Thambo JB, Taieb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649–51.

    Article  CAS  PubMed  Google Scholar 

  24. Yu Y, Varughese J, Brown LF, Mulliken JB, Bischoff J. Increased Tie2 expression, enhanced response to angiopoietin-1, and dysregulated angiopoietin-2 expression in hemangioma-derived endothelial cells. Am J Pathol. 2001;159(6):2271–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Perry DK, Hand WL, Edmondson DE, Lambeth JD. Role of phospholipase D-derived diradylglycerol in the activation of the human neutrophil respiratory burst oxidase. Inhibition by phosphatidic acid phosphohydrolase inhibitors. J Immunol. 1992;149(8):2749–58.

    CAS  PubMed  Google Scholar 

  26. Papakonstantinou E, Aletras AJ, Glass E, Tsogas P, Dionyssopoulos A, Adjaye J, Fimmel S, Gouvousis P, Herwig R, Lehrach H, Zouboulis CC, Karakiulakis G. Matrix metalloproteinases of epithelial origin in facial sebum of patients with acne and their regulation by isotretinoin. J Invest Dermatol. 2005;125(4):673–84.

    Article  CAS  PubMed  Google Scholar 

  27. Eady EA, Bojar RA, Jones CE, Cove JH, Holland KT, Cunliffe WJ. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin-resistant propionibacteria. Br J Dermatol. 1996;134(1):107–13.

    Article  CAS  PubMed  Google Scholar 

  28. Nickoloff BJ, Bonish BK, Marble DJ, Schriedel KA, DiPietro LA, Gordon KB, Lingen MW. Lessons learned from psoriatic plaques concerning mechanisms of tissue repair, remodeling, and inflammation. J Investig Dermatol Symp Proc. 2006;11(1):16–29.

    Article  CAS  PubMed  Google Scholar 

  29. Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, Berse B, Dvorak HF. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med. 1994;180(3):1141–6.

    Article  CAS  PubMed  Google Scholar 

  30. Markham T, Mullan R, Golden-Mason L, Rogers S, Bresnihan B, Fitzgerald O, Fearon U, Veale DJ. Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy. J Am Acad Dermatol. 2006;54(6):1003–12.

    Article  PubMed  Google Scholar 

  31. Chien AL, Elder JT, Ellis CN. Ustekinumab: a new option in psoriasis therapy. Drugs. 2009;69(9):1141–52.

    Article  CAS  PubMed  Google Scholar 

  32. Arbiser JL, Govindarajan B, Battle TE, Lynch R, Frank DA, Ushio-Fukai M, Perry BN, Stern DF, Bowden GT, Liu A, Klein E, Kolodziejski PJ, Eissa NT, Hossain CF, Nagle DG. Carbazole is a naturally occurring inhibitor of angiogenesis and inflammation isolated from antipsoriatic coal tar. J Invest Dermatol. 2006;126(6):1396–402.

    Article  CAS  PubMed  Google Scholar 

  33. Harada K, Baillie R, Lu S, Syrjanen S, Schor AM. VEGF expression in skin warts. Relevance to angiogenesis and vasodilation. Arch Dermatol Res. 2001;293(5):233–8.

    Article  CAS  PubMed  Google Scholar 

  34. Harada K, Lu S, Chisholm DM, Syrjanen S, Schor AM. Angiogenesis and vasodilation in skin warts. Association with HPV infection. Anticancer Res. 2000;20(6B):4519–23.

    CAS  PubMed  Google Scholar 

  35. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Low JA, Mackey HM, Yauch RL, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366(23):2171–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Miura H, Kusakabe Y, Sugiyama C, Kawamatsu M, Ninomiya Y, Motoyama J, Hino A. Shh and Ptc are associated with taste bud maintenance in the adult mouse. Mech Dev. 2001;106(1-2):143–5.

    Article  CAS  PubMed  Google Scholar 

  37. Hernandez-Pigeon H, Jean C, Charruyer A, Haure MJ, Baudouin C, Charveron M, Quillet-Mary A, Laurent G. UVA induces granzyme B in human keratinocytes through MIF: implication in extracellular matrix remodeling. J Biol Chem. 2007;282(11):8157–64.

    Article  CAS  PubMed  Google Scholar 

  38. Klafter R, Arbiser JL. Regulation of angiogenesis and tumorigenesis by signal transduction cascades: lessons from benign and malignant endothelial tumors. J Investig Dermatol Symp Proc. 2000;5(1):79–82.

    Article  CAS  PubMed  Google Scholar 

  39. Burnworth B, Arendt S, Muffler S, Steinkraus V, Brocker EB, Birek C, Hartschuh W, Jauch A, Boukamp P. The multi-step process of human skin carcinogenesis: a role for p53, cyclin D1, hTERT, p16, and TSP-1. Eur J Cell Biol. 2007;86(11-12):763–80.

    Article  CAS  PubMed  Google Scholar 

  40. Lacouture ME, Desai A, Soltani K, Petronic-Rosic V, Laumann AE, Ratain MJ, Stadler WM. Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol. 2006;31(6):783–5.

    Article  CAS  PubMed  Google Scholar 

  41. Dalton SJ, Whiting CV, Bailey JR, Mitchell DC, Tarlton JF. Mechanisms of chronic skin ulceration linking lactate, transforming growth factor-beta, vascular endothelial growth factor, collagen remodeling, collagen stability, and defective angiogenesis. J Invest Dermatol. 2007;127(4):958–68.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang ZL, Liu ZS, Sun Q. Expression of angiopoietins, Tie2 and vascular endothelial growth factor in angiogenesis and progression of hepatocellular carcinoma. World J Gastroenterol. 2006;12(26):4241–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris 3rd HA, Falchook G, Algazi A, Lewis K, Long GV, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bhandarkar SS, Jaconi M, Fried LE, Bonner MY, Lefkove B, Govindarajan B, Perry BN, Parhar R, Mackelfresh J, Sohn A, Stouffs M, Knaus U, Yancopoulos G, Reiss Y, Benest AV, Augustin HG, et al. Fulvene-5 potently inhibits NADPH oxidase 4 and blocks the growth of endothelial tumors in mice. J Clin Invest. 2009;119(8):2359–65.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

J.L.A. was supported by the grants RO1 AR47901 and P30 AR42687 from the Emory Skin Disease Research Core Center of the National Institutes of Health, as well as a Veterans Administration Merit Award.

Author information

Authors and Affiliations

  1. Department of Dermatology, Emory University, Atlanta, GA, USA

    Michael Y. Bonner MD

  2. Department of Dermatology, Atlanta Veterans Administration Medical Center, Emory University, 1690 Parliament Point, Atlanta, GA, USA

    Jack L. Arbiser MD, PhD, MSc

Authors
  1. Michael Y. Bonner MD
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  2. Jack L. Arbiser MD, PhD, MSc
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Corresponding author

Correspondence to Jack L. Arbiser MD, PhD, MSc .

Editor information

Editors and Affiliations

  1. School of Medicine, University of Maryland Baltimore, Baltimore, Maryland, USA

    Anthony A. Gaspari

  2. Department of Dermatology, University of Texas Health Science Center, Houston, Texas, USA

    Stephen K. Tyring

  3. Department of Dermatology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Daniel H. Kaplan

Questions

Questions

  1. 1.

    Which of the following is not an important growth factor for endothelial cells?

    1. A.

      angiopoietin-2

    2. B.

      basic fibroblast growth factor

    3. C.

      cyclooxygenase-2

    4. D.

      platelet-derived growth factor

    5. E.

      prostaglandin E-2

  2. 2.

    Which signaling pathway does not active vascular endothelial growth factor (VEGF)?

    1. A.

      hypoxia-inducible factor (HIF)

    2. B.

      interferon (IFN) alpha

    3. C.

      mammalian target of rapamycin (mTOR)

    4. D.

      mitogen-activated protein kinase (MAPK)

    5. E.

      mitogen-activated protein kinase kinase (MAPKK)

  3. 3.

    Overexpression of which of the following angiogenesis factors is not involved in melanoma progression?

    1. A.

      Ang-2

    2. B.

      FGF-2

    3. C.

      IL-8

    4. D.

      TRAIL

    5. E.

      VEGF-A

  4. 4.

    Mutations involving activation of which pathway accounts for most neovascular formation in humans?

    1. A.

      bFGF

    2. B.

      IFN alpha

    3. C.

      PI3K/akt

    4. D.

      reactive oxygen species/rac

    5. E.

      Raf

  5. 5.

    Which of the following is true of angiopoietin (ang)-1?

    1. A.

      it has antagonistic activity to ang-2

    2. B.

      it binds Tie-2 to stimulate vascular permeability

    3. C.

      it is stimulated by carbazole therapy

    4. D.

      it is stimulated by ultraviolet light therapy

    5. E.

      it is stimulated by methotrexate

Answers

  1. 1.

    A

  2. 2.

    B

  3. 3.

    D

  4. 4.

    C

  5. 5.

    A

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Bonner, M.Y., Arbiser, J.L. (2017). Angiogenesis for the Clinician. In: Gaspari, A., Tyring, S., Kaplan, D. (eds) Clinical and Basic Immunodermatology. Springer, Cham. https://doi.org/10.1007/978-3-319-29785-9_11

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  • DOI: https://doi.org/10.1007/978-3-319-29785-9_11

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  • Online ISBN: 978-3-319-29785-9

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